Advertisement

Calcified Tissue International

, Volume 86, Issue 6, pp 421–435 | Cite as

Adverse Effects of Bisphosphonates

  • Bo AbrahamsenEmail author
REVIEW

Abstract

Use of bisphosphonates has been growing steadily in the last decade. This follows the introduction of simpler dosing regimes, the availability of lower-priced generics, and concerns about the safety of hormone-replacement therapy. Bisphosphonates have a relatively good safety record and are tolerated by the majority of patients, but serious adverse events have been recorded in some cases. Only the most common of adverse effects are robustly observable in clinical trials. In general, studies were not powered to detect effects that were lower in incidence than fractures. This review of adverse events in bisphosphonate-treated patients was based on published information from case reports, case series, claims databases, national databases, surveys, adverse event reporting databases, and single or pooled clinical trials. The most common acute adverse events with bisphosphonates for osteoporosis are gastrointestinal discomfort and acute influenza-like illness. Renal complications are very rare with oral bisphosphonates and rare with i.v. bisphosphonates when used appropriately. Based on our current knowledge, skeletal events in the form of osteonecrosis of the jaw and atypical fragility fractures are rare compared with the risk of osteoporotic fractures, at least in patients with the same risk of fractures as those in the phase III trials. It is biologically plausible that atypical fragility fractures could follow from suppression of bone remodeling, but high-quality studies proving causality are lacking. Physicians are advised to critically reassess BMD and risk profile after 3–5 years of therapy to avoid treatment in patients at low risk.

Keywords

Bisphosphonate Bone turnover Remodeling Osteoporosis Mechanical loading Exercise 

References

  1. 1.
    Watts NB, Harris ST (1990) Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 323:73–79PubMedGoogle Scholar
  2. 2.
    Storm T, Thamsborg G, Steiniche T, Genant HK, Sørensen OH (1990) Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 322:1265–1272PubMedCrossRefGoogle Scholar
  3. 3.
    Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW, Dequeker J, Favus M (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 333:1437–1443PubMedCrossRefGoogle Scholar
  4. 4.
    Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535–1541PubMedCrossRefGoogle Scholar
  5. 5.
    Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082PubMedCrossRefGoogle Scholar
  6. 6.
    Abrahamsen B, Vestergaard P (2009) Declining incidence of hip fractures and the extent of use of anti-osteoporotic therapy in Denmark 1997–2006. Osteoporos Int 21:373–380PubMedCrossRefGoogle Scholar
  7. 7.
    Waller PC, Evans SJ, Beard K (2006) Drug safety and the media. Br J Clin Pharmacol 61:123–126PubMedCrossRefGoogle Scholar
  8. 8.
    Russell RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759PubMedCrossRefGoogle Scholar
  9. 9.
    Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH (2006) Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38:617–627PubMedCrossRefGoogle Scholar
  10. 10.
    Lawson MA, Xia Z, Barnett BL, Triffitt JT, Phipps RJ, Dunford JE, Locklin RM, Ebetino FH, Russell RG (2009) Differences between bisphosphonates in binding affinities for hydroxyapatite. J Biomed Mater Res B Appl Biomater 92B:149–155Google Scholar
  11. 11.
    Arrain Y, Masud T (2009) Bisphosphonates and osteonecrosis of the jaw—current thoughts. Dent Update 36:415–419PubMedGoogle Scholar
  12. 12.
    Tosteson AN, Grove MR, Hammond CS, Moncur MM, Ray GT, Hebert GM, Pressman AR, Ettinger B (2003) Early discontinuation of treatment for osteoporosis. Am J Med 115:209–216PubMedCrossRefGoogle Scholar
  13. 13.
    Graham DY (2002) What the gastroenterologist should know about the gastrointestinal safety profiles of bisphosphonates. Dig Dis Sci 47:1665–1678PubMedCrossRefGoogle Scholar
  14. 14.
    Ettinger B, Pressman A, Schein J, Chan J, Silver P, Connolly N (1998) Alendronate use among 812 women: prevalence of gastrointestinal complaints, noncompliance with patient instructions, and discontinuation. J Manag Care Pharm 4:488–492Google Scholar
  15. 15.
    Graham DY, Malaty HM (1999) Alendronate gastric ulcers. Aliment Pharmacol Ther 13:515–519PubMedCrossRefGoogle Scholar
  16. 16.
    Lanza FL, Hunt RH, Thomson AB, Provenza JM, Blank MA (2000) Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology 119:631–638PubMedCrossRefGoogle Scholar
  17. 17.
    Thomson AB, Marshall JK, Hunt RH, Provenza JM, Lanza FL, Royer MG, Li Z, Blank MA (2002) 14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status. J Rheumatol 29:1965–1974PubMedGoogle Scholar
  18. 18.
    Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, Kagan R, Chen E, Petruschke RA, Thompson DE, de Papp AE (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20:141–151PubMedCrossRefGoogle Scholar
  19. 19.
    Cadarette SM, Katz JN, Brookhart MA, Sturmer T, Stedman MR, Levin R, Solomon DH (2009) Comparative gastrointestinal safety of weekly oral bisphosphonates. Osteoporos Int 20:1735–1747PubMedCrossRefGoogle Scholar
  20. 20.
    Wysowski DK (2009) Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:89–90PubMedCrossRefGoogle Scholar
  21. 21.
    Abrahamsen B, Eiken P, Eastell R (2009) More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:1789PubMedCrossRefGoogle Scholar
  22. 22.
    Solomon DH, Patrick A, Brookhart MA (2009) More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:1790Google Scholar
  23. 23.
    Vestergaard P, Schwartz K, Pinholt EM, Rejnmark L, Mosekilde L (2010) Gastric and esophagus events before and during treatment of osteoporosis. Calcif Tissue Int 86:110–115PubMedCrossRefGoogle Scholar
  24. 24.
    Peter CP, Handt LK, Smith SM (1998) Esophageal irritation due to alendronate sodium tablets: possible mechanisms. Dig Dis Sci 43:1998–2002PubMedCrossRefGoogle Scholar
  25. 25.
    Reszka AA, Halasy-Nagy J, Rodan GA (2001) Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation. Mol Pharmacol 59:193–202PubMedGoogle Scholar
  26. 26.
    Lichtenberger LM, Romero JJ, Gibson GW, Blank MA (2000) Effect of bisphosphonates on surface hydrophobicity and phosphatidylcholine concentration of rodent gastric mucosa. Dig Dis Sci 45:1792–1801PubMedCrossRefGoogle Scholar
  27. 27.
    Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953PubMedCrossRefGoogle Scholar
  28. 28.
    De Vries F, Cooper AL, Cockle SM, van Staa TP, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998PubMedCrossRefGoogle Scholar
  29. 29.
    Thiebaud D, Sauty A, Burckhardt P, Leuenberger P, Sitzler L, Green JR, Kandra A, Zieschang J, Ibarra dP (1997) An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 61:386–392PubMedCrossRefGoogle Scholar
  30. 30.
    Dicuonzo G, Vincenzi B, Santini D, Avvisati G, Rocci L, Battistoni F, Gavasci M, Borzomati D, Coppola R, Tonini G (2003) Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 23:649–654PubMedCrossRefGoogle Scholar
  31. 31.
    Thompson K, Rogers MJ (2004) Statins prevent bisphosphonate-induced gamma, delta-T-cell proliferation and activation in vitro. J Bone Miner Res 19:278–288PubMedCrossRefGoogle Scholar
  32. 32.
    Bock O, Boerst H, Thomasius FE, Degner C, Stephan-Oelkers M, Valentine SM, Felsenberg D (2007) Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention. J Musculoskelet Neuronal Interact 7:144–148PubMedGoogle Scholar
  33. 33.
    Wysowski DK, Chang JT (2005) Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 165:346–347PubMedCrossRefGoogle Scholar
  34. 34.
    Demonaco HJ (2009) Patient- and physician-oriented Web sites and drug surveillance: bisphosphonates and severe bone, joint, and muscle pain. Arch Intern Med 169:1164–1166PubMedCrossRefGoogle Scholar
  35. 35.
    Gwynne Jones DP, Savage RL, Highton J (2008) Alendronate-induced synovitis. J Rheumatol 35:537–538PubMedGoogle Scholar
  36. 36.
    Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R (2009) Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital. Drug Saf 32:775–785PubMedCrossRefGoogle Scholar
  37. 37.
    Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, van der Meulen MC, Lorich DG, Lane JM (2009) Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 20:1353–1362PubMedCrossRefGoogle Scholar
  38. 38.
    Abrahamsen B, Eiken P, Eastell R (2009) Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 24:1095–1102PubMedCrossRefGoogle Scholar
  39. 39.
    Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG (2008) Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 22:346–350PubMedCrossRefGoogle Scholar
  40. 40.
    Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D, Tugwell P (2008) Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev CD001155Google Scholar
  41. 41.
    Schilcher J, Aspenberg P (2009) Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthop 80:413–415PubMedCrossRefGoogle Scholar
  42. 42.
    Boivin G, Farlay D, Bala Y, Doublier A, Meunier PJ, Delmas PD (2009) Influence of remodeling on the mineralization of bone tissue. Osteoporos Int 20:1023–1026PubMedCrossRefGoogle Scholar
  43. 43.
    Allen MR, Reinwald S, Burr DB (2008) Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment. Calcif Tissue Int 82:354–360PubMedCrossRefGoogle Scholar
  44. 44.
    Weinstein RS (2000) True strength. J Bone Miner Res 15:621–625PubMedCrossRefGoogle Scholar
  45. 45.
    Leeming DJ, Henriksen K, Byrjalsen I, Qvist P, Madsen SH, Garnero P, Karsdal MA (2009) Is bone quality associated with collagen age? Osteoporos Int 20:1461–1470PubMedCrossRefGoogle Scholar
  46. 46.
    Nyman JS, Roy A, Tyler JH, Acuna RL, Gayle HJ, Wang X (2007) Age-related factors affecting the postyield energy dissipation of human cortical bone. J Orthop Res 25:646–655PubMedCrossRefGoogle Scholar
  47. 47.
    Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD (2008) Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int 19:329–337PubMedCrossRefGoogle Scholar
  48. 48.
    Visekruna M, Wilson D, McKiernan FE (2008) Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 93:2948–2952PubMedCrossRefGoogle Scholar
  49. 49.
    Whyte MP (2009) Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res 24:1132–1134PubMedCrossRefGoogle Scholar
  50. 50.
    Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301PubMedCrossRefGoogle Scholar
  51. 51.
    Odvina CV, Levy S, Rao S, Zerwekh JE, Sudhaker RD (2009) Unusual mid-shaft fractures during long term bisphosphonate therapy. Clin Endocrinol (Oxf). PMID:19302584Google Scholar
  52. 52.
    Cheung RK, Leung KK, Lee KC, Chow TC (2007) Sequential non-traumatic femoral shaft fractures in a patient on long-term alendronate. Hong Kong Med J 13:485–489PubMedGoogle Scholar
  53. 53.
    Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE (2009) Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res 24:1736–1740PubMedCrossRefGoogle Scholar
  54. 54.
    Burr DB, Turner CH, Naick P, Forwood MR, Ambrosius W, Hasan MS, Pidaparti R (1998) Does microdamage accumulation affect the mechanical properties of bone? J Biomech 31:337–345PubMedCrossRefGoogle Scholar
  55. 55.
    Carter DR, Hayes WC (1977) Compact bone fatigue damage—I. Residual strength and stiffness. J Biomech 10:325–337PubMedCrossRefGoogle Scholar
  56. 56.
    Allen MR, Burr DB (2008) Skeletal microdamage: less about biomechanics and more about remodeling. Clin Rev Bone Miner Metab 6:24–30Google Scholar
  57. 57.
    Garrison JG, Slaboch CL, Niebur GL (2009) Density and architecture have greater effects on the toughness of trabecular bone than damage. Bone 44:924–929PubMedCrossRefGoogle Scholar
  58. 58.
    Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB (2001) Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28:524–531PubMedCrossRefGoogle Scholar
  59. 59.
    Siris ES, Simon JA, Barton IP, McClung MR, Grauer A (2008) Effects of risedronate on fracture risk in postmenopausal women with osteopenia. Osteoporos Int 19:681–686PubMedCrossRefGoogle Scholar
  60. 60.
    Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491PubMedCrossRefGoogle Scholar
  61. 61.
    Morag Y, Morag-Hezroni M, Jamadar DA, Ward BB, Jacobson JA, Zwetchkenbaum SR, Helman J (2009) Bisphosphonate-related osteonecrosis of the jaw: a pictorial review. Radiographics 29:1971–1984PubMedCrossRefGoogle Scholar
  62. 62.
    Hoefert S, Schmitz I, Tannapfel A, Eufinger H (2009) Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin Oral Investig. PMID:19536569Google Scholar
  63. 63.
    Burr DB, Allen MR (2009) Mandibular necrosis in beagle dogs treated with bisphosphonates. Orthod Craniofac Res 12:221–228PubMedCrossRefGoogle Scholar
  64. 64.
    Don-Wauchope AC, Cole DE (2009) The (mis) use of bone resorption markers in the context of bisphosphonate exposure, dental surgery and osteonecrosis of the jaw. Clin Biochem 42:1194–1196PubMedCrossRefGoogle Scholar
  65. 65.
    Allen MR (2009) Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench. Cells Tissues Organs 189:289–294PubMedCrossRefGoogle Scholar
  66. 66.
    Amagase K, Hayashi S, Nishikawa K, Aihara E, Takeuchi K (2007) Impairment of gastric ulcer healing by alendronate, a nitrogen-containing bisphosphonate, in rats. Dig Dis Sci 52:1879–1889PubMedCrossRefGoogle Scholar
  67. 67.
    Aragon-Ching JB, Ning YM, Chen CC, Latham L, Guadagnini JP, Gulley JL, Arlen PM, Wright JJ, Parnes H, Figg WD, Dahut WL (2009) Higher incidence of osteonecrosis of the jaw (ONJ) in patients with metastatic castration resistant prostate cancer treated with anti-angiogenic agents. Cancer Invest 27:221–226PubMedCrossRefGoogle Scholar
  68. 68.
    Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW (2008) Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 66:767–775PubMedCrossRefGoogle Scholar
  69. 69.
    Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836PubMedCrossRefGoogle Scholar
  70. 70.
    Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44:857–869PubMedCrossRefGoogle Scholar
  71. 71.
    Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis CG, Boukovinas I, Koloutsos GE, Teleioudis Z, Kitikidou K, Paraskevopoulos P, Zervas K, Antoniades K (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27:5356–5362PubMedCrossRefGoogle Scholar
  72. 72.
    Jung TI, Hoffmann F, Glaeske G, Felsenberg D (2010) Disease-specific risk for an osteonecrosis of the jaw under bisphosphonate therapy. J Cancer Res Clin Oncol 136:363–370PubMedCrossRefGoogle Scholar
  73. 73.
    Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, Hutchinson M, Lathon PV, Sanchez G, Silver P, Chandra M, McCloskey CA, Staffa JA, Willy M, Selby JV, Go AS (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243–253PubMedCrossRefGoogle Scholar
  74. 74.
    Mavrokokki T, Cheng A, Stein B, Goss A (2007) Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 65:415–423PubMedCrossRefGoogle Scholar
  75. 75.
    Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes S, Lowry B, Shuler CF (2009) Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry. J Am Dent Assoc 140:61–66PubMedGoogle Scholar
  76. 76.
    Cartsos VM, Zhu S, Zavras AI (2008) Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714, 217 people. J Am Dent Assoc 139:23–30PubMedGoogle Scholar
  77. 77.
    Pazianas M, Blumentals WA, Miller PD (2008) Lack of association between oral bisphosphonates and osteonecrosis using jaw surgery as a surrogate marker. Osteoporos Int 19:773–779PubMedCrossRefGoogle Scholar
  78. 78.
    Marx RE, Cillo JE Jr, Ulloa JJ (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65:2397–2410PubMedCrossRefGoogle Scholar
  79. 79.
    Kunchur R, Need A, Hughes T, Goss A (2009) Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67:1167–1173PubMedCrossRefGoogle Scholar
  80. 80.
    Baim S, Miller PD (2009) Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res 24:561–574PubMedCrossRefGoogle Scholar
  81. 81.
    Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, Beneton MN, Gertz BJ, Sciberras DG, Holland SD, Orgee J, Coombes GM, Rogers SR, Porras AG (1997) Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 12:1700–1707PubMedCrossRefGoogle Scholar
  82. 82.
    Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 67:2–12PubMedGoogle Scholar
  83. 83.
    Price PA, Roublick AM, Williamson MK (2006) Artery calcification in uremic rats is increased by a low protein diet and prevented by treatment with ibandronate. Kidney Int 70:1577–1583PubMedCrossRefGoogle Scholar
  84. 84.
    Delibasi T, Emral R, Erdogan MF, Kamel N (2007) Effects of alendronate sodium therapy on carotid intima media thickness in postmenopausal women with osteoporosis. Adv Ther 24:319–325PubMedCrossRefGoogle Scholar
  85. 85.
    Ylitalo R, Kalliovalkama J, Wu X, Kankaanranta H, Salenius JP, Sisto T, Lahteenmaki T, Ylitalo P, Porsti I (1998) Accumulation of bisphosphonates in human artery and their effects on human and rat arterial function in vitro. Pharmacol Toxicol 83:125–131PubMedCrossRefGoogle Scholar
  86. 86.
    Shimshi M, Abe E, Fisher EA, Zaidi M, Fallon JT (2005) Bisphosphonates induce inflammation and rupture of atherosclerotic plaques in apolipoprotein-E null mice. Biochem Biophys Res Commun 328:790–793PubMedCrossRefGoogle Scholar
  87. 87.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822PubMedCrossRefGoogle Scholar
  88. 88.
    Cummings SR, Schwartz AV, Black DM (2007) Alendronate and atrial fibrillation. N Engl J Med 356:1895–1896PubMedCrossRefGoogle Scholar
  89. 89.
    Karam R, Camm J, McClung M (2007) Yearly zoledronic acid in postmenopausal osteoporosis. N Engl J Med 357:712–713PubMedGoogle Scholar
  90. 90.
    Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809PubMedCrossRefGoogle Scholar
  91. 91.
    Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM (2008) Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 168:826–831PubMedCrossRefGoogle Scholar
  92. 92.
    Sorensen HT, Christensen S, Mehnert F, Pedersen L, Chapurlat RD, Cummings SR, Baron JA (2008) Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 336:813–816PubMedCrossRefGoogle Scholar
  93. 93.
    Abrahamsen B, Eiken P, Brixen K (2009) Atrial fibrillation in fracture patients treated with oral bisphosphonates. J Intern Med 265:581–592PubMedCrossRefGoogle Scholar
  94. 94.
    From AM, Hyder JA, Kearns AM, Bailey KR, Pellikka PA (2007) Relationship between low bone mineral density and exercise-induced myocardial ischemia. Mayo Clin Proc 82:679–685PubMedCrossRefGoogle Scholar
  95. 95.
    Courtney AE, Maxwell AP (2009) Chronic kidney disease and bisphosphonate treatment: are prescribing guidelines unnecessarily restrictive? Postgrad Med J 85:327–330PubMedCrossRefGoogle Scholar
  96. 96.
    Toussaint ND, Elder GJ, Kerr PG (2009) Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue. Clin J Am Soc Nephrol 4:221–233PubMedCrossRefGoogle Scholar
  97. 97.
    Troehler U, Bonjour JP, Fleisch H (1985) Renal transport of bisphosphonates: accumulation by renal cortical slices enhanced by calcium phosphate ions. J Lab Clin Med 106:23–29PubMedGoogle Scholar
  98. 98.
    Chang JT, Green L, Beitz J (2003) Renal failure with the use of zoledronic acid. N Engl J Med 349:1676–1679PubMedCrossRefGoogle Scholar
  99. 99.
    Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, Kuhn JA, Dratch AD, D’Agati VD (2001) Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 12:1164–1172PubMedGoogle Scholar
  100. 100.
    Markowitz GS, Fine PL, D’Agati VD (2002) Nephrotic syndrome after treatment with pamidronate. Am J Kidney Dis 39:1118–1122PubMedCrossRefGoogle Scholar
  101. 101.
    Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D’Agati VD (2003) Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 64:281–289PubMedCrossRefGoogle Scholar
  102. 102.
    Perazella MA, Markowitz GS (2008) Bisphosphonate nephrotoxicity. Kidney Int 74:1385–1393PubMedCrossRefGoogle Scholar
  103. 103.
    Pascual J, Torrealba J, Myers J, Tome S, Samaniego M, Musat A, Djamali A (2007) Collapsing focal segmental glomerulosclerosis in a liver transplant recipient on alendronate. Osteoporos Int 18:1435–1438PubMedCrossRefGoogle Scholar
  104. 104.
    Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE (2005) Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res 20:2105–2115PubMedCrossRefGoogle Scholar
  105. 105.
    Miller PD (2005) Treatment of osteoporosis in chronic kidney disease and end-stage renal disease. Curr Osteoporos Rep 3:5–12PubMedCrossRefGoogle Scholar
  106. 106.
    Mitchell DY, St Peter JV, Eusebio RA, Pallone KA, Kelly SC, Russell DA, Nesbitt JD, Thompson GA, Powell JH (2000) Effect of renal function on risedronate pharmacokinetics after a single oral dose. Br J Clin Pharmacol 49:215–222PubMedCrossRefGoogle Scholar
  107. 107.
    French DD, Margo CE (2008) Postmarketing surveillance rates of uveitis and scleritis with bisphosphonates among a national veteran cohort. Retina 28:889–893PubMedCrossRefGoogle Scholar
  108. 108.
    Leung S, Ashar BH, Miller RG (2005) Bisphosphonate-associated scleritis: a case report and review. South Med J 98:733–735PubMedCrossRefGoogle Scholar
  109. 109.
    Fraunfelder FW, Fraunfelder FT, Jensvold B (2003) Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 135:219–222PubMedCrossRefGoogle Scholar
  110. 110.
    Richards JC, Wiffen SJ (2006) Corneal graft rejection precipitated by uveitis secondary to alendronate sodium therapy. Cornea 25:1100–1101PubMedCrossRefGoogle Scholar
  111. 111.
    Siris ES (1993) Bisphosphonates and iritis. Lancet 341:436–437PubMedCrossRefGoogle Scholar
  112. 112.
    Musette P, Brandi ML, Cacoub P, Kaufman JM, Rizzoli R, Reginster JY (2010) Treatment of osteoporosis: recognizing and managing cutaneous adverse reactions and drug-induced hypersensitivity. Osteoporos Int 21:723–732PubMedCrossRefGoogle Scholar
  113. 113.
    Phillips E, Knowles S, Weber E, Shear NH (1998) Skin reactions associated with bisphosphonates: a report of 3 cases and an approach to management. J Allergy Clin Immunol 102:697–698PubMedCrossRefGoogle Scholar
  114. 114.
    Barrera BA, Wilton L, Harris S, Shakir SA (2005) Prescription-event monitoring study on 13, 164 patients prescribed risedronate in primary care in England. Osteoporos Int 16:1989–1998PubMedCrossRefGoogle Scholar
  115. 115.
    Biswas PN, Wilton LV, Shakir SA (2003) Pharmacovigilance study of alendronate in England. Osteoporos Int 14:507–514PubMedCrossRefGoogle Scholar
  116. 116.
    Kazmi AS, Wall BM (2007) Reversible congestive heart failure related to profound hypocalcemia secondary to hypoparathyroidism. Am J Med Sci 333:226–229PubMedCrossRefGoogle Scholar
  117. 117.
    Kashyap AS, Kashyap S (2000) Hypoparathyroidism unmasked by alendronate. Postgrad Med J 76:417–418PubMedCrossRefGoogle Scholar
  118. 118.
    Maclsaac RJ, Seeman E, Jerums G (2002) Seizures after alendronate. J R Soc Med 95:615–616PubMedCrossRefGoogle Scholar
  119. 119.
    Meek SE, Nix K (2007) Hypocalcemia after alendronate therapy in a patient with celiac disease. Endocr Pract 13:403–407PubMedGoogle Scholar
  120. 120.
    Whitson HE, Lobaugh B, Lyles KW (2006) Severe hypocalcemia following bisphosphonate treatment in a patient with Paget’s disease of bone. Bone 39:954–958PubMedCrossRefGoogle Scholar
  121. 121.
    Zuradelli M, Masci G, Biancofiore G, Gullo G, Scorsetti M, Navarria P, Tancioni F, Berlusconi M, Giordano L, Santoro A (2009) High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid. Oncologist 14:548–556PubMedCrossRefGoogle Scholar
  122. 122.
    Yanik B, Turkay C, Atalar H (2007) Hepatotoxicity induced by alendronate therapy. Osteoporos Int 18:829–831PubMedCrossRefGoogle Scholar
  123. 123.
    Halabe A, Lifschitz BM, Azuri J (2000) Liver damage due to alendronate. N Engl J Med 343:365–366PubMedCrossRefGoogle Scholar
  124. 124.
    Armamento-Villareal R, Napoli N, Panwar V, Novack D (2006) Suppressed bone turnover during alendronate therapy for high-turnover osteoporosis. N Engl J Med 355:2048–2050PubMedCrossRefGoogle Scholar
  125. 125.
    Lee P, van der WH, Seibel MJ (2007) Looking beyond low bone mineral density: multiple insufficiency fractures in a woman with post-menopausal osteoporosis on alendronate therapy. J Endocrinol Invest 30:590–597PubMedGoogle Scholar
  126. 126.
    Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (2008) An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 39:224–231PubMedCrossRefGoogle Scholar
  127. 127.
    Sayed-Noor AS, Sjoden GO (2009) Case reports: two femoral insufficiency fractures after long-term alendronate therapy. Clin Orthop Relat Res 467:1921–1926PubMedCrossRefGoogle Scholar
  128. 128.
    Goddard MS, Reid KR, Johnston JC, Khanuja HS (2009) Atraumatic bilateral femur fracture in long-term bisphosphonate use. Orthopedics 32:pii. doi: 10.3928/01477447-20090624-27
  129. 129.
    Edwards MH, McCrae FC, Young-Min SA (2010) Alendronate-related femoral diaphysis fracture-what should be done to predict and prevent subsequent fracture of the contralateral side? Osteoporos Int 21:701–703PubMedCrossRefGoogle Scholar
  130. 130.
    Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333:1437–1443PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Internal Medicine and Endocrinology FCopenhagen University Hospital GentofteHellerupDenmark
  2. 2.Institute of Clinical Research, Odense Patient Data Exploratory Network (OPEN)University of Southern DenmarkOdense CDenmark

Personalised recommendations